Here, we show a facile and one-step electrospinning strategy to fabricate multi-region scaffolds that display two main fibrillar microstructure arrays: honeycomb-like (HC) and randomly-oriented (RO), which are joined by an interface that aims to facilitate a smooth physical transition between them. Relevant design parameters including macropore size, fiber diameter, piezoelectric and mechanical properties were investigated. Our results show that polycaprolactone (PCL)-based scaffolds exhibited macropores in the HC and interface regions that could be tailored (from 867 ± 74 to 424 ± 27 μm and from 101 ± 10 to 80 ± 10, respectively) by increasing the electrospun polymer volume, while their fiber diameter distribution was not altered in a significant manner. Moreover, the local mechanical properties of these scaffolds changed in a discreet fashion according to each region's geometry, ensuring physical properties gradation from the RO to the HC zones. The versatility of this scaffold fabrication method was extended to the use of polyvinylidine fluoride (PVDF): while the macrostructural and mechanical properties were preserved, different fiber size distribution between the RO (353 ± 53 nm) and HC (251 ± 37 nm) regions as well as dissimilar fiber orientation were found, correlating with a variation in the piezoelectricity (β-phase fraction) within the scaffold. This fabrication technique could represent another alternative to engineer biocompatible multi-tissue systems with tunable structure and mechanics.